Human Rabies: a 2016 Update

  • Alan C. JacksonEmail author
Central Nervous System Infections (K Bloch, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Central Nervous System Infections


Rabies is a zoonotic disease that is usually transmitted to humans by animal bites. Dogs are the most important vector worldwide. There are encephalitic and paralytic forms of the disease. There are differences in the clinical features of the disease acquired from dogs and bats. Neuroimaging is non-specific. Confirmatory diagnostic laboratory tests for rabies include detection of neutralizing anti-rabies virus antibodies in serum or cerebrospinal fluid and rabies virus antigen or RNA in tissues or fluids. Rabies is preventable after recognized exposures with wound cleansing and administration of rabies vaccine and rabies immune globulin. Rabies is virtually always fatal after clinical disease develops, and there have only been rare survivors. The Milwaukee protocol, which includes therapeutic coma, has been shown to be ineffective and should no longer be used. The development of novel therapeutic approaches may depend on a better understanding of basic mechanisms underlying the disease.


Encephalitis Hydrophobia Paralytic rabies Rabies Rabies virus Zoonosis 


Compliance with Ethical Standards

Conflicts of Interest

Dr Jackson declares that he has no conflicts of interests.

Human and Animal Rights and Informed Consent

This article does not contain any reports of new studies with human or animal subjects performed by the author.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hampson K, Coudeville L, Lembo T, Sambo M, Kieffer A, Attlan M, et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis. 2015;9:e0003709.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Monroe BP, Yager P, Blanton J, Birhane MG, Wadhwa A, Orciari L, et al. Rabies surveillance in the United States during 2014. J Am Vet Med Assoc. 2016;248:777–88.CrossRefPubMedGoogle Scholar
  3. 3.
    Fu ZF, Jackson AC. Neuronal dysfunction and death in rabies virus infection. J Neurovirol. 2005;11:101–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Scott CA, Rossiter JP, Andrew RD, Jackson AC. Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome in experimental rabies in yellow fluorescent protein-expressing transgenic mice. J Virol. 2008;82:513–21.CrossRefPubMedGoogle Scholar
  5. 5.
    Jackson AC, Kammouni W, Zherebitskaya E, Fernyhough P. Role of oxidative stress in rabies virus infection of adult mouse dorsal root ganglion neurons. J Virol.2010;84:4697--705.Google Scholar
  6. 6.
    Alandijany T, Kammouni W, Roy Chowdhury SK, Fernyhough P, Jackson AC. Mitochondrial dysfunction in rabies virus infection of neurons. J Neurovirol. 2013;19:537–49.CrossRefPubMedGoogle Scholar
  7. 7.
    Kammouni W, Wood H, Saleh A, Appolinario CM, Fernyhough P, Jackson AC. Rabies virus phosphoprotein interacts with mitochondrial complex I and induces mitochondrial dysfunction and oxidative stress. J Neurovirol. 2015;21:370–82.CrossRefPubMedGoogle Scholar
  8. 8.
    Warrell DA. The clinical picture of rabies in man. Trans R Soc Trop Med Hyg. 1976;70:188–95.CrossRefPubMedGoogle Scholar
  9. 9.
    Warrell DA, Davidson NM, Pope HM, Bailie WE, Lawrie JH, Ormerod LD, et al. Pathophysiologic studies in human rabies. Am J Med. 1976;60:180–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Tirawatnpong S, Hemachudha T, Manutsathit S, Shuangshoti S, Phanthumchinda K, Phanuphak P. Regional distribution of rabies viral antigen in central nervous system of human encephalitic and paralytic rabies. J Neurol Sci. 1989;92:91–9.CrossRefPubMedGoogle Scholar
  11. 11.•
    Udow SJ, Marrie RA, Jackson AC. Clinical features of dog- and bat-acquired rabies in humans. Clin Infect Dis. 2013;57:689–96. This article highlights important differences in the clinical presentation of human rabies acquired from dogs and bats. CrossRefPubMedGoogle Scholar
  12. 12.
    Feasby TE, Gilbert JJ, Brown WF, Bolton CF, Hahn AF, Koopman WF, et al. An acute axonal form of Guillain-Barre polyneuropathy. Brain. 1986;109:1115–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Griffin JW, Li CY, Ho TW, Tian M, Gao CY, Xue P, et al. Pathology of the motor-sensory axonal Guillain-Barre syndrome. Ann Neurol. 1996;39:17–28.CrossRefPubMedGoogle Scholar
  14. 14.
    Sheikh KA, Ramos-Alvarez M, Jackson AC, Li CY, Asbury AK, Griffin JW. Overlap of pathology in paralytic rabies and axonal Guillain-Barré syndrome. Ann Neurol. 2005;57:768–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barre syndrome. Ann Neurol. 1990;27(Suppl):S21–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Laothamatas J, Hemachudha T, Mitrabhakdi E, Wannakrairot P, Tulayadaechanont S. MR imaging in human rabies. A J N R Am J Neuroradiol. 2003;24:1102–9.Google Scholar
  17. 17.
    Anderson LJ, Nicholson KG, Tauxe RV, Winkler WG. Human rabies in the United States, 1960 to 1979: epidemiology, diagnosis, and prevention. Ann Intern Med. 1984;100:728–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Bryceson ADM, Greenwood BM, Warrell DA, Davidson NM, Pope HM, Lawrie JH, et al. Demonstration during life of rabies antigen in humans. J Inf Dis. 1975;131:71–4.CrossRefGoogle Scholar
  19. 19.
    Warrell MJ, Looareesuwan S, Manatsathit S, White NJ, Phuapradit P, Vejjajiva A, et al. Rapid diagnosis of rabies and post-vaccinal encephalitides. Clin Exp Immunol. 1988;71:229–34.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Noah DL, Drenzek CL, Smith JS, Krebs JW, Orciari L, Shaddock J, et al. Epidemiology of human rabies in the United States, 1980 to 1996. Ann Intern Med. 1998;128:922–30.CrossRefPubMedGoogle Scholar
  21. 21.
    Mathuranayagam D, Rao PV. Antemortem diagnosis of human rabies by corneal impression smears using immunofluorescent technique. Indian J Med Res. 1984;79:463–7.PubMedGoogle Scholar
  22. 22.
    Koch FJ, Sagartz JW, Davidson DE, Lawhaswasdi K. Diagnosis of human rabies by the cornea test. Am J Clin Pathol. 1975;63:509–15.CrossRefPubMedGoogle Scholar
  23. 23.
    Familusi JB, Osunkoya BO, Moore DL, Kemp GE, Fabiyi A. A fatal human infection with Mokola virus. Am J Trop Med Hyg. 1972;21:959–63.PubMedGoogle Scholar
  24. 24.
    Meredith CD, Rossouw AP, Koch HP. An unusual case of human rabies thought to be of chiropteran origin. S Afr Med J. 1971;45:767–9.PubMedGoogle Scholar
  25. 25.
    Paweska JT, Blumberg LH, Liebenberg C, Hewlett RH, Grobbelaar AA, Leman PA, et al. Fatal human infection with rabies-related Duvenhage virus. South Africa Emerg Infect Dis. 2006;12:1965–7.CrossRefPubMedGoogle Scholar
  26. 26.
    van Thiel PP, de Bie RM, Eftimov F, Tepaske R, Zaaijer HL, van Doornum GJ, et al. Fatal human rabies due to Duvenhage virus from a bat in Kenya: failure of treatment with coma-induction, ketamine, and antiviral drugs. PLoS Negl Trop Dis. 2009;3:e428.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Selimov MA, Tatarov AG, Botvinkin AD, Klueva EV, Kulikova LG, Khismatullina NA. Rabies-related Yuli virus; Identification with a panel of monoclonal antibodies. Acta Virol. 1989;33:542–6.PubMedGoogle Scholar
  28. 28.
    Bourhy H, Kissi B, Lafon M, Sacramento D, Tordo N. Antigenic and molecular characterization of bat rabies virus in Europe. J Clin Microbiol. 1992;30:2419–26.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Anonymous. Bat rabies in the Union of Soviet Socialist Republics. Rabies Bull Europe. 1986;10:12–4.Google Scholar
  30. 30.
    Botvinkin AD, Selnikova OP, Antonova LA, Moiseeva AB, Nesterenko EY, Gromashevsky LV. Human rabies case caused from a bat bite in Ukraine. Rabies Bull Europe. 2005;29:5–7.Google Scholar
  31. 31.
    Roine RO, Hillbom M, Valle M, Haltia M, Ketonen L, Neuvonen E, et al. Fatal encephalitis caused by a bat-borne rabies-related virus: clinical findings. Brain. 1988;111:1505–16.CrossRefPubMedGoogle Scholar
  32. 32.
    Nathwani D, McIntyre PG, White K, Shearer AJ, Reynolds N, Walker D, et al. Fatal human rabies caused by European bat lyssavirus type 2a infection in Scotland. Clin Infect Dis. 2003;37:598–601.CrossRefPubMedGoogle Scholar
  33. 33.
    Fooks AR, McElhinney LM, Pounder DJ, Finnegan CJ, Mansfield K, Johnson N, et al. Case report: isolation of a European bat lyssavirus type 2a from a fatal human case of rabies encephalitis. J Med Virol. 2003;71:281–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Samaratunga H, Searle JW, Hudson N. Non-rabies lyssavirus human encephalitis from fruit bats: Australian bat lyssavirus (pteropid lyssavirus) infection. Neuropathol Appl Neurobiol. 1998;24:331–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Hanna JN, Carney IK, Smith GA, Tannenberg AEG, Deverill JE, Botha JA, et al. Australian bat lyssavius infection: a second human case, with a long incubation period. Med J Aust. 2000;172:597–9.PubMedGoogle Scholar
  36. 36.
    Francis JR, Nourse C, Vaska VL, Calvert S, Northill JA, McCall B, et al. Australian bat lyssavirus in a child: the first reported case. Pediatrics. 2014;133:e1063–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Leonova GN, Belikov SI, Kondratov IG, Krylova NV, Pavlenko EV, Romanova EV, et al. A fatal case of bat lyssavirus infection in Primorye Territory of the Russian Far East. Rabies Bull Europe. 2009;33:5–8.Google Scholar
  38. 38.
    Jackson AC, Warrell MJ, Rupprecht CE, Ertl HCJ, Dietzschold B, O'Reilly M, et al. Management of rabies in humans. Clin Infect Dis. 2003;36:60–3.CrossRefPubMedGoogle Scholar
  39. 39.
    Willoughby Jr RE, Tieves KS, Hoffman GM, Ghanayem NS, Amlie-Lefond CM, Schwabe MJ, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. 2005;352:2508–14.CrossRefPubMedGoogle Scholar
  40. 40.
    Hu WT, Willoughby Jr RE, Dhonau H, Mack KJ. Long-term follow-up after treatment of rabies by induction of coma (letter). N Engl J Med. 2007;357:945–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Jackson AC. Recovery from rabies (editorial). N Engl J Med. 2005;352:2549–50.CrossRefPubMedGoogle Scholar
  42. 42.•
    Jackson AC. Current and future approaches to the therapy of human rabies. Antiviral Res. 2013;99:61–7. This review article summarizes current knowledge relevant to treating human patients with rabies and provides important evidence about the failure of the Milwaukee protocol. CrossRefPubMedGoogle Scholar
  43. 43.••
    Zeiler FA, Jackson AC. Critical appraisal of the Milwaukee protocol for rabies: this failed approach should be abandoned. Can J Neurol Sci. 2016;43:44–51. This article is a detailed evaluation of the Milwaukee protocol that highlights its poor scientific rationale, flaws, and lack of therapeutic efficacy. CrossRefPubMedGoogle Scholar
  44. 44.
    Hattwick MAW, Weis TT, Stechschulte CJ, Baer GM, Gregg MB. Recovery from rabies: a case report. Ann Intern Med. 1972;76:931–42.CrossRefPubMedGoogle Scholar
  45. 45.
    Porras C, Barboza JJ, Fuenzalida E, Adaros HL, Oviedo AM, Furst J. Recovery from rabies in man. Ann Intern Med. 1976;85:44–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Tillotson JR, Axelrod D, Lyman DO. Rabies in a laboratory worker - New York. MMWR.1977; 26:183-4.Google Scholar
  47. 47.
    Tillotson JR, Axelrod D, Lyman DO. Follow-up on rabies - New York. MMWR.1977; 26:249-50.Google Scholar
  48. 48.
    Alvarez L, Fajardo R, Lopez E, Pedroza R, Hemachudha T, Kamolvarin N, et al. Partial recovery from rabies in a nine-year-old boy. Pediatr Infect Dis J. 1994;13:1154–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Madhusudana SN, Nagaraj D, Uday M, Ratnavalli E, Kumar MV. Partial recovery from rabies in a six-year-old girl (letter). Int J Infect Dis. 2002;6:85–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Ministerio da Saude in Brazil. Rabies, human survival, bat - Brazil: (Pernambuco). ProMED-mail 2008; 20081114.3599. Accessed 10 Feb 2009.Google Scholar
  51. 51.
    Karahocagil MK, Akdeniz H, Aylan O, Sünnetçioglu M, Ün H, Yapici K, et al. Complete recovery from clinical rabies: case report. Turkiye Klinikleri J Med Sci. 2013;33:547–52.CrossRefGoogle Scholar
  52. 52.
    Netravathi M, Udani V, Mani RS, Gadad V, Ashwini MA, Bhat M, et al. Unique clinical and imaging findings in a first ever documented PCR positive rabies survival patient: a case report. J Clin Virol. 2015;70:83–8.CrossRefGoogle Scholar
  53. 53.
    de Souza A, Madhusudana SN. Survival from rabies encephalitis. J Neurol Sci. 2014;339:8–14.CrossRefPubMedGoogle Scholar
  54. 54.
    Weyer J, Msimang-Dermaux V, Paweska JT, le Roux K, Govender P, Coertse J, et al. A case of human survival of rabies, South Africa. South Afr J Infect Dis. 2016;31:66–8.Google Scholar
  55. 55.
    Galvez S, Basque M, Contreras L, Merino C, Ahumada R, Jamett J, et al.: Survivor of rabies encephalitis in Chile. Platform presentation at the XXIVth International Meeting on Research Advances and Rabies Control in the Americas in Toronto, Ontario, Canada on October 27, 2013. Research Advances and Rabies Control in the Americas 2013.Google Scholar
  56. 56.
    Thakur BS. 2nd rabies survivor in country at P’kula hospital. Hindustan times. Panchkula: HT Media Limited; 2014.Google Scholar
  57. 57.
    Kumar KV, Ahmad FM, Dutta V. Pituitary cachexia after rabies encephalitis (letter). Neurol India. 2015;63:255–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Karande S, Muranjan M, Mani RS, Anand AM, Amoghimath R, Sankhe S, et al. Atypical rabies encephalitis in a six-year-old boy: clinical, radiological and laboratory findings. Int J Infect Dis. 2015;36:1–3.CrossRefPubMedGoogle Scholar
  59. 59.
    Manoj S, Mukherjee A, Johri S, Kumar KV. Recovery from rabies, a universally fatal disease. Mil Med Res. 2016;3:21–0089.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Holzmann-Pazgal G, Wanger A, Degaffe G, Rose C, Heresi G, Amaya R, et al. Presumptive abortive human rabies - Texas, 2009. MMWR.2010;59:185-90.Google Scholar
  61. 61.
    Wiedeman J, Plant J, Glaser C, Messenger S, Wadford D, Sheriff H, et al. Recovery of a patient from clinical rabies - California, 2011. MMWR.2012;61:61-5.Google Scholar
  62. 62.
    Rawat AK, Rao SK. Survival of a rabies patient (letter). Indian Pediatr. 2011;48:574.PubMedGoogle Scholar
  63. 63.
    Jackson AC, Fu ZF. Pathogenesis. In: Jackson AC, editor. Rabies: Scientific basis of the disease and its management. 3rd ed. Oxford: Elsevier Academic Press; 2013. p. 299–349.CrossRefGoogle Scholar
  64. 64.
    Jackson AC: Therapy of human rabies, in Rabies: scientific basis of the disease and its management, Third Edition, edited by AC Jackson. Elsevier Academic Press. Oxford: UK; 2013. p. 573–87.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Internal Medicine (Neurology)University of Manitoba, Health Sciences CentreWinnipegCanada
  2. 2.Department of Medical MicrobiologyUniversity of Manitoba, Health Sciences CentreWinnipegCanada

Personalised recommendations